EP3622953B1 - Combination treatment of cancer - Google Patents

Combination treatment of cancer Download PDF

Info

Publication number
EP3622953B1
EP3622953B1 EP19205104.3A EP19205104A EP3622953B1 EP 3622953 B1 EP3622953 B1 EP 3622953B1 EP 19205104 A EP19205104 A EP 19205104A EP 3622953 B1 EP3622953 B1 EP 3622953B1
Authority
EP
European Patent Office
Prior art keywords
cancer
vrac
present disclosure
hormone agent
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP19205104.3A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP3622953A1 (en
Inventor
Nils Aage Brünner
Palle Christophersen
Jan Stenvang
Jens Lichtenberg
Annemette Thougaard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scandion Oncology AS
Original Assignee
Scandion Oncology AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scandion Oncology AS filed Critical Scandion Oncology AS
Priority to RS20210510A priority Critical patent/RS61786B1/sr
Priority to EP21162597.5A priority patent/EP3854393A1/en
Priority to PL19205104T priority patent/PL3622953T3/pl
Priority to SI201730713T priority patent/SI3622953T1/sl
Publication of EP3622953A1 publication Critical patent/EP3622953A1/en
Application granted granted Critical
Publication of EP3622953B1 publication Critical patent/EP3622953B1/en
Priority to HRP20210572TT priority patent/HRP20210572T1/hr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present disclosure relates to treatment of cancer, in particular to methods of sensitising cancer cells to an anti-cancer treatment by administering an effective amount of a VRAC modulator.
  • Cancer is an overwhelming burden to our society with approximately 14 million new cases of cancer diagnosed in 2014. Despite the introduction of many new treatment modalities/options, de novo or acquired resistance to the applied treatments still represents the major cause of death from cancer.
  • VRACs Volume Regulated Anion Channels
  • An important function of VRAC is cell volume regulation. Upon swelling of the cell in hypotonic solution these channels are activated and chloride ions flow out of the cell in parallel with potassium ions (via potassium channels) and water, thereby restoring the original cell volume.
  • NS3728 Endovion; SCO-101
  • SCO-101 is a potent orally active VRAC blocker.
  • VRAC modulators including NS3728, and their use in the treatment of sickle cell anaemia.
  • VRAC modulators including NS3728, and their use in the treatment of diseases responsive to anti-angiogenic therapy, in particular anti-metastatic treatment.
  • Chemotherapeutic treatment of metastatic colorectal cancer is generally based on the anti-metabolite drug 5-fluorouracil (5FU) combined with either the DNA-binding agent oxaliplatin (e.g. FOLFOX regimen) or the topoisomerase I inhibitor irinotecan (e.g. FOLFIRI regimen) and often administered in combination with biological treatment, e.g. EGFR targeting drugs or anti-angiogenic drugs.
  • 5FU 5-fluorouracil
  • BC Breast cancer
  • adjuvant treatment of BC the most often used drugs are cytotoxic drugs including anthracyclines (topoisomerase 2 inhibitors) and taxanes. These drugs are most often administered in conjunction with cyclophosphamide.
  • adjuvant treatment most often includes anti-estrogens such as aromatase inhibitors, estrogen receptor antagonists (tamoxifen and fulvestrant).
  • anti-estrogens such as aromatase inhibitors, estrogen receptor antagonists (tamoxifen and fulvestrant).
  • approximately 18-20% of patients receiving adjuvant or neoadjuvant systemic anti-cancer treatment will experience a disease recurrence.
  • the present disclosure provides a novel treatment regimen for cancer and is particularly suitable for treatment of chemotherapy-resistant cancers.
  • the treatment regimen of the present disclosure comprises treatment with a compound capable of modulating the activity of volume regulated anion channels (VRAC), i.e. the VRAC modulator Endovion (NS3728).
  • VRAC volume regulated anion channels
  • NS3728 the VRAC modulator Endovion
  • Co-treatment with NS3728 has surprisingly been shown to enhance the effect of an anti-cancer treatment.
  • co-treatment with a VRAC modulator is shown to be capable of re-sensitising chemotherapy resistant cancer cells to treatment with certain chemotherapeutic agents.
  • the present invention relates to a VRAC modulator of formula I, or a pharmaceutically acceptable salt thereof,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a VRAC modulator of formula I,
  • the present invention relates to a composition
  • a composition comprising an effective amount of a VRAC modulator of formula I, or a pharmaceutically acceptable salt thereof, and an effective amount of an anti-hormone agent for use as a medicament, wherein the anti-hormone agent is selected from the group consisting of:
  • the present invention relates to a kit of parts comprising a VRAC modulator of formula I,
  • the present inventors have surprisingly found that co-treatment of cancer with a VRAC modulator and an anti-cancer therapy, such as a chemotherapeutic agent, has increased efficacy as compared to monotherapy, and furthermore re-sensitises chemoresistant cancer cells to treatment, and therefore propose a new treatment regimen for cancer wherein a VRAC modulator is administered to potentiate the therapeutic effect of an anti-cancer treatment and/or sensitise the cancer cells to the anti-cancer treatment.
  • a VRAC modulator is administered to potentiate the therapeutic effect of an anti-cancer treatment and/or sensitise the cancer cells to the anti-cancer treatment.
  • VRAC Volume regulated anion channels
  • VRAC Volume-Sensitive Organic Osmolyte Anion Channel
  • VSOAC Volume Sensitive Outward Rectifier
  • VDAC Voltage Dependent Anion Channel
  • HSVOR Human Volume-Sensitive Outward Rectifier
  • VRCIC Volume Regulated Chloride Channel
  • VRAC is an almost ubiquitously distributed anion channel, which is activated by cell swelling and/or a decrease in intracellular ionic strength. It is the channel mediating increased anion conductance during Regulatory Volume Decrease (RVD).
  • RVD Regulatory Volume Decrease
  • VRAC Activation of VRAC is obligatory dependent on the presence of intracellular ATP and complex intracellular signalling cascades involving protein kinases support the activation process.
  • the VRAC modulator is a VRAC blocker.
  • VRAC blocker is used interchangeably herein with the term "VRAC inhibitor”.
  • a VRAC blocker is a compound that inhibits the transmembrane transport of chloride or any other anion or neutral molecule in response to cell swelling or decrease in intracellular ionic strength.
  • a compound acting as a VRAC inhibitor binds to the channel protein and exerts its inhibiting effect discernible via one or more of the methods of measuring VRAC function as described herein.
  • Inhibiting compounds may act via one or more theoretical mode-of-actions (MOA), the main groups of which are:
  • VRAC blockers The elucidation of the detailed MOA for a particular compound is a very challenging task, and may require combination of high-sensitivity functional measurements (e.g. single channel recordings as mentioned herein) and high-resolution structural information (e.g. crystallography, sequence analyses, mutagenesis analyses etc.). In the present case it is not unequivocally determined which MOAs are responsible for the VRAC inhibiting effects of the VRAC modulators mentioned herein. Thus, they are collectively referred to as VRAC blockers.
  • VRAC blocker The potential of a given substance to act as a VRAC blocker may be determined using standard laboratory test methods, such as
  • VRAC activity it is necessary to activate the channel protein by swelling the cell (e.g. by exposure to a hypotonic extracellular Ringers solution) or by making the intracellular solution hypertonic or low in ionic strength (only few technologies allow that, i.e. the whole cell patch clamp describes under 1.a below)
  • VRAC activity is most directly registered by electrophysiological methods that allow direct measurements of the swelling activated transmembrane anion current at a fixed membrane potential (voltage clamp). The possibilities are:
  • VRAC expression can be measured for example by qPCR, in situ hybridization or antibodies.
  • the VRAC blocker is a diphenyl urea derivative such as those described in WO 98/47879 and/or WO 00/24707 .
  • the VRAC blockers show IC50-values of less than 10 ⁇ M, such as less than 1000 nM, for example less than 100 nM, such as less than 50 nM, for example less than 10 nM for in vitro inhibition according to the standard test methods.
  • the VRAC blocker has an IC50 of 5 ⁇ M or less, such as 3 ⁇ M or less, for example 1 ⁇ M or less, such as 0.5 ⁇ M or less, for example 0.1 ⁇ M or less, such as 10 nM or less, for example 5 nM or less.
  • the VRAC blocker has an IC50 of 2 ⁇ M or less, such as 1 ⁇ M or less, such as 0.5 ⁇ M or less, for example 0.1 ⁇ M or less, such as 10 nM or less, for example 5 nM or less. In a preferred embodiment of the present disclosure, the VRAC blocker has an IC50 of 0.5 ⁇ M or less.
  • VRAC blocker is a compound of general formula I
  • the VRAC blocker is a compound of general formula I
  • R 2 represents tetrazolyl
  • R 3 , R 4 , R 5 , R 6 , R 12 , R 13 , R 14 , R 15 , and R 16 independently of each other represent hydrogen, halo, trifluoromethyl, or nitro.
  • the compound of general formula I, R 3 , R 5 , and R 6 represent hydrogen; and R 4 represents halo, such as bromine.
  • the compound of general formula I, R 3 , R 4 , R 5 and R 6 represent hydrogen.
  • R 3 , R 5 , and R 6 represent hydrogen; and R 4 represents -NR a R b , such as amino.
  • R 3 , R 5 , and R 6 represent hydrogen; and R 4 represents -NR a -CO-R b , such as acetylamino.
  • R 3 , R 5 , and R 6 represent hydrogen; and R 4 represents phenyl substituted with trifluoromethyl, nitro or -CO-NHR c ; wherein R c is phenyl.
  • R 4 represents phenyl substituted with trifluoromethyl, such as 4-trifluoromethylphenyl.
  • R 4 represents phenyl substituted with nitro, such as 3-nitrophenyl.
  • R 4 represents phenyl substituted with -CO-NHR c , such as anilinocarbonylphenyl, in particular 4-anilinocarbonylphenyl.
  • R 3 , R 5 , and R 6 represent hydrogen; and R 4 represents phenyl substituted with -CO-O-R c or -CO-NR'R".
  • R 4 represents phenyl substituted with -CO-O-R c , wherein R c is hydrogen.
  • R4 represents phenyl substituted with -CO-NR'R", such as 4-dimethylcarbamoylphenyl or 4-(4-methyl-1-piperazine-carbonyl)-phenyl.
  • R 15 represents trifluoromethyl. In a special embodiment of the present disclosure, R 15 represents trifluoromethyl and R 12 , R 13 , R 14 and R 16 represent hydrogen. In a further embodiment of the present disclosure R 13 represents trifluoromethyl. In a special embodiment of the present disclosure, R 13 and R 15 represent trifluoromethyl and R 12 , R 14 and R 16 represent hydrogen.
  • R 16 represents trifluoromethyl. In a special embodiment of the present disclosure, R 16 represents trifluoromethyl and R 12 , R 13 , R 14 and R 15 represent hydrogen. In a still further embodiment of the present disclosure, R 15 represents halo, such as chloro or bromo. In a special embodiment of the present disclosure, R 15 represents halo, such as chloro or bromo, and R 12 , R 13 , R 14 and R 16 represent hydrogen. In a further embodiment of the present disclosure, R 13 and R 15 represent halo, such as chloro, and R 12 , R 14 and R 16 represent hydrogen. In a still further embodiment of the present disclosure, R 14 and R 15 represent halo, such as chloro, and R 12 , R 13 and R 16 represent hydrogen.
  • R 16 represents halo, such as fluoro. In a special embodiment of the present disclosure, R 16 represents halo, such as fluoro, and R 12 , R 13 , R 14 and R 15 represent hydrogen. In a still further embodiment of the present disclosure, R 16 represents alkyl, such as methyl or ethyl. In a special embodiment of the present disclosure, R 16 represents alkyl, such as methyl or ethyl, and R 12 , R 13 , R 14 and R 15 represent hydrogen.
  • R 14 represents nitro. In a special embodiment of the present disclosure, R 14 represents nitro, and R 12 , R 13 , R 15 and R 16 represent hydrogen. In a still further embodiment of the present disclosure, R 14 represents alkylcarbonyl, such as acetyl. In a special embodiment of the present disclosure, R 14 represents alkylcarbonyl, such as acetyl, and R 12 , R 13 , R 15 and R 16 represent hydrogen.
  • R 15 represents phenyl. In a further embodiment of the present disclosure, R 14 represents phenyl. In a special embodiment of the present disclosure, one of R 14 or R 15 represents phenyl, and the remaining of R 12 , R 13 , R 14 , R 15 and R 16 represent hydrogen. In a still further embodiment of the present disclosure, R 15 represents pyridyl, such as pyridin-3-yl. In a special embodiment of the present disclosure, R 15 represents pyridyl, such as pyridin-3-yl, and R 12 , R 13 , R 14 and R 16 represent hydrogen.
  • R 15 and R 16 together with the phenyl ring to which they are attached form a naphthyl ring.
  • R 14 and R 15 together with the phenyl ring to which they are attached form an indanyl ring.
  • the compound of general formula I is selected from
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the VRAC blocker is NS3728: or a pharmaceutically acceptable salt thereof.
  • NS3728 is also known as Endovion and SCO-101.
  • NS3728 is a potent orally active VRAC blocker with an IC 50 of 0.40 ⁇ M ( Helix et al., J Membrane Biol. 196, 2003 ).
  • the VRAC blocker is NS3623: or a pharmaceutically acceptable salt thereof.
  • NS3623 is a VRAC blocker with an IC 50 of 1.8 ⁇ M ( Helix et al., J Membrane Biol. 196, 2003 ).
  • the VRAC blocker is NS3749: or a pharmaceutically acceptable salt thereof.
  • NS3749 is a VRAC blocker with an IC 50 of 1.4 ⁇ M ( Helix et al., J Membrane Biol. 196, 2003 ).
  • the VRAC blocker is tamoxifen (TMX): or a pharmaceutically acceptable salt thereof.
  • the VRAC blocker is not tamoxifen.
  • the anti-cancer treatment is an anti-estrogen, more particularly tamoxifen
  • the VRAC blocker is not tamoxifen.
  • VRAC modulators are described in EP 2 919 009 .
  • halo represents fluoro, chloro, bromo or iodo.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to six carbon atoms (C 1-6 -alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a C 1-4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a C 1-3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • heteroaryl group designates an aromatic mono-, bi- or poly-heterocyclic group, which holds one or more heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S).
  • Preferred monocyclic heteroaryl groups of the disclosure include aromatic 5- and 6 membered heterocyclic monocyclic groups, including furanyl, in particular 2- or 3-furanyl; thienyl, in particular 2 or 3-thienyl; pyrrolyl (azolyl), in particular 1,2 or 3-pyrrolyl; oxazolyl, in particular oxazol-2,4 or 5-yl; thiazolyl, in particular thiazol-2,4 or 5-yl; imidazolyl, in particular 1,2 or 4-imidazolyl; pyrazolyl, in particular 1,3 or 4-pyrazolyl; isoxazolyl, in particular isoxazol-3,4 or 5-yl; isothiazolyl, in particular isothiazol-3,4 or 5-yl; oxadiazolyl, in particular 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazol-3,4 or 5-yl; triazolyl, in particular 1,2,3-, 1,
  • 5- to 7-membered heterocyclic rings comprising one nitrogen atom include for example, but not limited to, pyrolidine, piperidine, homopiperidine, pyrroline, tetrahydropyridine, pyrazolidine, imidazolidine, piperazine, homopiperazine, and morpholine.
  • VRAC blocker as described herein may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fuma
  • acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound for use according to the present disclosure and its pharmaceutically acceptable acid addition salt.
  • Examples of pharmaceutically acceptable cationic salts of a chemical compound of the present disclosure include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysine, and the ammonium salt, and the like, of a chemical compound of the present disclosure containing an anionic group.
  • Such cationic salts may be formed by procedures well known and described in the art.
  • onium salts of N-containing compounds are also contemplated as pharmaceutically acceptable salts (aza-onium salts).
  • Preferred azaonium salts include the alkyl-onium salts, in particular the methyl- and the ethylonium salts; the cycloalkyl-onium salts, in particular the cyclopropyl-onium salts; and the cycloalkylalkyl-onium salts, in particular the cyclopropyl-methyl-onium salts.
  • the present disclosure relates a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a VRAC modulator and a chemotherapeutic agent.
  • VRAC blocker and/or the chemotherapeutic agent as disclosed herein may be administered in the form of the raw chemical compounds, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the present disclosure provides pharmaceutical compositions comprising the VRAC blocker according to the disclosure, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients know and used in the art.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • the present disclosure provides pharmaceutical compositions comprising more than one compound or prodrug for use according to the disclosure, such as two different compounds or prodrugs for use according to the disclosure.
  • compositions of the disclosure may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the disclosure, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • the VRAC blocker of the disclosure together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • VRAC blocker as disclosed herein can be administered in a wide variety of oral and parenteral dosage forms.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the VRAC blocker according to the present disclosure may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the VRAC blocker may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the VRAC blocker may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatine, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • compositions adapted to give sustained release of the VRAC active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • the VRAC inhibitor is formulated for topical administration.
  • a therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition.
  • Therapeutic efficacy and toxicity e.g. ED 50 and LD 50
  • ED 50 and LD 50 may be determined by standard pharmacological procedures in cell cultures or experimental animals.
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD 50 /ED 50 .
  • Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
  • the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
  • the actual dosage of the VRAC modular and/or the anti-cancer agent depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances to produce the desired therapeutic effect.
  • the VRAC blocker may be administered in one or several doses per day.
  • Exemplary ranges are from 10-200 mg/day p.o. (per oral) administered in one or two doses, such as from 25-50 mg p.o. twice a day.
  • the subject to be treated according to the present disclosure may be any human or animal subject, preferably a human suffering from cancer.
  • the present disclosure relates to sensitising cancer cells to an anti-cancer treatment or potentiating the therapeutic effect of an anti-cancer treatment.
  • the cancer is resistant to treatment with a chemotherapeutic agent. If a cancer is resistant, co-treatment with a VRAC blocker is capable of re-sensitising the cancer to the chemotherapeutic agent in question.
  • Resistance of cancers may be either de novo resistance or acquired resistance.
  • a cancer is regarded as resistant to a particular anti-cancer therapy if a patient treated with the clinically accepted dosage of the anti-cancer agent does not respond as expected to the anti-cancer agent, i.e. in case of worsening, growth, or spread of the cancer (progressive disease). Whether a cancer is drug-sensitive or resistant can be determined by the skilled person.
  • the cancer to be treated according to the present disclosure may be selected from the group consisting of lung cancer (non small cell lung cancer and small cell lung cancer), Glioblastomas, Head and neck cancers, Malignant melanomas, Basal cell skin cancer, Squamous cell skin cancer, Breast cancer, Liver cancer, Pancreatic cancer, Prostate cancer, Colorectal cancer, anal cancer, Cervix uteri cancer, Bladder cancer, Corpus uteri cancer, Ovarian cancer, Gall bladder cancer, Sarcomas, Leukemia's (myeloid and lymphatic), Lymphomas, Myelomatosis.
  • lung cancer non small cell lung cancer and small cell lung cancer
  • Glioblastomas head and neck cancers
  • Malignant melanomas Basal cell skin cancer
  • Squamous cell skin cancer Squamous cell skin cancer
  • Breast cancer Liver cancer
  • Pancreatic cancer Pancreatic cancer
  • Prostate cancer Pancreatic cancer
  • Colorectal cancer anal cancer
  • the cancer is metastatic.
  • the cancer is colorectal cancer.
  • the cancer is metastatic colorectal cancer.
  • the cancer is breast cancer.
  • the cancer is metastatic breast cancer.
  • the cancer is glioblastoma. In one embodiment of the present disclosure the cancer is a solid tumour such as a solid tumour selected from sarcoma, carcinoma and lymphoma.
  • the cancer is not a solid tumour.
  • the cancer may be a hematological malignancy including but not limited to leukemia.
  • the cancer is prostate cancer, such as metastatic prostate cancer.
  • the cancer is a steroid hormone receptor positive cancer, e.g. an estrogen receptor positive cancer, a progesterone receptor positive cancer or an androgen receptor positive cancer.
  • a steroid hormone receptor positive cancer e.g. an estrogen receptor positive cancer, a progesterone receptor positive cancer or an androgen receptor positive cancer.
  • An anti-cancer treatment according to the present disclosure may be treatment with one or more chemotherapeutic agents and/or radiation therapy.
  • the anti-cancer treatment encompasses treatment with a chemotherapeutic agent.
  • Chemotherapy drugs can be divided into groups based on factors such as how they work, their chemical structure, and their relationship to other drugs. Some drugs act in more than one way, and may belong to more than one group.
  • the anti-cancer treatment of the present disclosure encompasses treatment with more than one chemotherapeutic agent.
  • the anti-cancer treatment is a chemotherapeutic agent selected from the group consisting of a cytotoxic agent, a cytostatic agent, an anti-hormone agent, an anti-angiogenic agent and an anti-cancer biologic agent with a well-defined target.
  • the chemotherapeutic agent is a cytotoxic agent or a cytostatic agent.
  • the anti-cancer treatment is a chemotherapeutic agent and the VRAC modulator is co-administered with the chemotherapeutic agent.
  • the VRAC modulator may be administered prior to, simultaneously with and/or after initiation of the anti-cancer treatment. In one embodiment of the present disclosure the VRAC modulator is administered prior to initiation of anti-cancer treatment. In one embodiment of the present disclosure the VRAC modulator is administered simultaneously with the anti-cancer treatment.
  • Co-administration refers to administration of a VRAC modulator and an anti-cancer treatment to a subject, wherein the VRAC modulator may be administered prior to, simultaneously with and/or after the anti-cancer treatment.
  • VRAC modulator potentiates the effect of the anti-cancer treatment.
  • the effect of treatment with a VRAC blocker and an anti-cancer treatment is additive or synergistic.
  • the effect of treatment is synergistic.
  • administration of the VRAC modulator allows for administration of the anti-cancer treatment at a lower than normal dose, i.e. a dose that would normally be considered a sub-therapeutic dosage.
  • administering enhances the clinical effect of the anti-cancer treatment.
  • Clinical effect may be determined by the clinician.
  • the anti-cancer treatment is a chemotherapeutic agent selected from the group consisting of topoisomerase inhibitors, anti-hormone agents, alkylating agents, antimetabolites, anti-tumour antibiotics, mitotic inhibitors, corticosteroids, targeted anti-cancer therapies, differentiating agents, and immunotherapy.
  • the chemotherapeutic agent is an alkylating agent.
  • Alkylating agents directly damage DNA (the genetic material in each cell) to keep the cell from reproducing. These drugs work in all phases of the cell cycle and are used to treat many different cancers, including glioblastoma, leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary.
  • Alkylating agents are divided into different classes, including:
  • the alkylating agent is selected from the group consisting of Nitrogen mustards, Nitrosoureas, Alkyl sulfonates, Triazines, Ethylenimine.
  • the alkylating agent is a triazine, such as temozolomide.
  • platinum drugs such as cisplatin, carboplatin, and oxaliplatin
  • alkylating agents because they kill cells in a similar way.
  • platinum drugs are not considered alkylating agents.
  • the anti-cancer treatment does not comprise or consist of treatment with a metal-based anticancer drug, such as a platinum, ruthenium, gold or titanium-based anticancer drug.
  • a metal-based anticancer drug such as a platinum, ruthenium, gold or titanium-based anticancer drug.
  • the anti-cancer treatment does not comprise or consist of treatment with a platinum-based anticancer drug, such as cisplatin, carboplatin, oxaliplatin or nedaplatin.
  • a platinum-based anticancer drug such as cisplatin, carboplatin, oxaliplatin or nedaplatin.
  • an alkylating agent is combined with a VRAC modulator for the treatment of glioblastoma, in particular glioblastoma, which is resistant to treatment with alkylating agents.
  • the alkylating agent is a triazine, such temozolomide (temodal)
  • the VRAC modulator is NS3728
  • the cancer to be treated is glioblastoma, in particular temozolomide-resistant glioblastoma.
  • the chemotherapeutic agent is an antimetabolite.
  • Antimetabolites interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase, when the cell's chromosomes are being copied. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, e.g. colorectal cancer as well as other types of cancer.
  • the antimetabolite is selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), Capecitabine (Xeloda®), Cytarabine (Ara-C®), Floxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxyurea, Methotrexate, Pemetrexed (Alimta®).
  • the antimetabolite is 5-fluorouracil (5-FU).
  • an anti-metabolite is combined with a VRAC modulator for the treatment of colorectal cancer, in particular colorectal cancer which is resistant to treatment with anti-metabolites.
  • the colorectal cancer is metastatic colorectal cancer.
  • 5-FU is co-administered with a VRAC modulator, such as NS3728, for the treatment of colorectal cancer, in particular a 5-FU resistant colorectal cancer.
  • a VRAC modulator such as NS3728
  • the colorectal cancer is metastatic colorectal cancer.
  • the chemotherapeutic agent of the present disclosure is an anti-tumour antibiotic agent. In other embodiments of the present disclosure, the chemotherapeutic agent is not an anti-tumour antibiotic agent.
  • the anti-tumour antibiotic agent is an anthracycline.
  • Anthracyclines are anti-cancer antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. Anthracyclines are also capable of inhibiting topoisomerase II.
  • anthracyclines examples include:
  • Anti-tumor antibiotics that are not anthracyclines include:
  • the chemotherapeutic agent is a topoisomerase inhibitor, which may be a Topoisomerase I inhibitor or a Topoisomerase II inhibitor. These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied during the S phase. Topoisomerase inhibitors are used to treat colorectal cancer, certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers.
  • Topoisomerase inhibitors are grouped according to which type of enzyme they affect.
  • Topoisomerase I inhibitors include:
  • Topoisomerase II inhibitors include:
  • the topoisomerase inhibitor is a Topoisomerase I inhibitor, such as Irinotecan or its active metabolite SN-38.
  • the topoisomerase inhibitor is a Topoisomerase II inhibitor, such as an anthracycline.
  • a topoisomerase inhibitor such as a topoisomerase I inhibitor
  • a VRAC modulator for the treatment of colorectal cancer, in particular colorectal cancer which is resistant to treatment with said topoisomerase inhibitor.
  • the colorectal cancer is metastatic colorectal cancer.
  • irinotecan/SN-38 is co-administered with a VRAC modulator, such as NS3728, for the treatment of colorectal cancer, in particular an irinotecan/SN-38 resistant colorectal cancer.
  • a VRAC modulator such as NS3728
  • the colorectal cancer is metastatic colorectal cancer.
  • the chemotherapeutic agent is a mitotic inhibitor.
  • Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They work by stopping mitosis in the M phase of the cell cycle but can damage cells in all phases by keeping enzymes from making proteins needed for cell reproduction.
  • mitotic inhibitors examples include:
  • Mitotic inhibitors are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias.
  • the mitotic inhibitor is a taxane, such as paclitaxel or docetaxel.
  • a mitotic inhibitor is combined with a VRAC modulator for the treatment of breast cancer, in particular breast cancer which is resistant to treatment with mitotic inhibitors.
  • the breast cancer is metastatic breast cancer.
  • a taxane such as paclitaxel or docetaxel is co-administered with a VRAC modulator, such as NS3728, for the treatment of breast cancer, in particular a paclitaxel or docetaxel resistant breast cancer.
  • a VRAC modulator such as NS3728
  • the breast cancer is metastatic breast cancer.
  • the chemotherapeutic agent of the present disclosure is a corticosteroid.
  • Corticosteroids often simply called steroids, are natural hormones and hormone-like drugs that are useful in the treatment of many types of cancer, as well as other illnesses.
  • corticosteroids examples include:
  • Steroids are also commonly used to help prevent nausea and vomiting caused by chemotherapy. They are used before chemotherapy to help prevent severe allergic reactions, too.
  • the chemotherapeutic agent is not a corticosteroid.
  • Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories. Examples include drugs like L-asparaginase, which is an enzyme, and the proteasome inhibitor bortezomib (Velcade®).
  • the chemotherapeutic agent is a targeted anti-cancer agent, such as an antibody-based therapy which acts on a well-defined target or biologic pathway.
  • Examples of targeted therapies include:
  • the targeted anti-cancer therapy is an anti-angiogenesis agent, such as an anti-VEGF agent.
  • the anti-angiogenesis agent may be a humanised anti-VEGF monoclonal antibody, such as Avastin (Bevacizumab). If the anti-cancer therapy of the present disclosure is an anti-angiogenesis agent, the anti-angiogenesis agent is not a VRAC blocker such as NS3728.
  • the chemotherapeutic agent is not a targeted anti-cancer agent.
  • retinoids act on the cancer cells to make them mature into normal cells.
  • tretinoin ATRA or Atralin®
  • bexarotene Targretin®
  • Arsenox® arsenic trioxide
  • the chemotherapeutic agent is a differentiating agent. In some embodiments of the present disclosure the chemotherapeutic agent is not a differentiating agent.
  • the chemotherapeutic agent is an agent for anti-hormone therapy.
  • Drugs in this category are sex hormones, or hormone-like drugs, that change the action or production of female or male hormones. They are used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural sex hormones in the body. These cancer treatment hormones do not work in the same ways as standard chemotherapy drugs. They work by making the cancer cells unable to use the hormone they need to grow, or by preventing the body from making the hormone.
  • anti-hormone therapy examples include:
  • the anti-cancer treatment comprises anti-estrogen treatment.
  • Anti- estrogens also known as estrogen receptor antagonists or estrogen receptor blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body.
  • the anti-estrogen is fulvestrant.
  • the anti-estrogen is tamoxifen.
  • the anti-cancer treatment comprises anti-progestogen treatment.
  • Anti-progestogens, or anti-progestins, also known as progesterone receptor antagonists or progesterone blockers, are a class of drugs which prevent progestogens like progesterone from mediating their biological effects in the body.
  • anti-progestogens examples include mifepristone, ulipristal acetate, aglepristone, lilopristone and onapristone.
  • the anti-cancer treatment comprises anti-androgen treatment.
  • Anti-androgens also known as androgen receptor antagonists or testosterone blockers, are a class of drugs which prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body.
  • DHT dihydrotestosterone
  • the chemotherapeutic agent is not an anti-hormone agent.
  • Anti-hormone therapy is particularly useful for treatment of steroid hormone receptor positive cancers, for example anti-estrogens are used for treatment of ER positive breast or uterine cancer.
  • an anti-estrogen is co-administered with a VRAC modulator, such as NS3728, for the treatment of an ER positive cancer, such as an ER positive breast cancer.
  • a VRAC modulator such as NS3728
  • the breast cancer is metastatic breast cancer.
  • an anti-progestogen is co-administered with a VRAC modulator, such as NS3728, for the treatment of a PR positive cancer, such as a PR positive breast cancer.
  • a PR positive cancer such as a PR positive breast cancer.
  • the breast cancer is metastatic breast cancer.
  • an anti-androgen is co-administered with a VRAC modulator, such as NS3728, for the treatment of an AR positive cancer, such as an AR positive prostate cancer.
  • a VRAC modulator such as NS3728
  • an AR positive cancer such as an AR positive prostate cancer.
  • the prostate cancer is metastatic prostate cancer.
  • the chemotherapeutic agent is an immunotherapy agent.
  • Immunotherapy drugs are given to people with cancer to help their immune systems recognize and attack cancer cells.
  • Active immunotherapies stimulate the body's own immune system to fight the disease.
  • Passive immunotherapies do not rely on the body to attack the disease; they're immune system components (such as antibodies) created outside the body and given to fight the cancer.
  • active immunotherapies include:
  • the chemotherapeutic agent is a PD-1 or PD-L1 inhibitor, such as an antibody capable of inhibiting PD-1 or PD-L1.
  • Cancer vaccines are a type of active specific immunotherapy.
  • the chemotherapeutic agent is not an immunotherapy agent.
  • the anti-cancer treatment is radiation therapy.
  • Radiation therapy is therapy using ionizing radiation, generally as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumour recurrence after surgery to remove a primary malignant tumour (for example, early stages of breast cancer). Radiation therapy is synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. Doses and treatment schedules of radiation therapy vary depending on the type and stage of cancer being treated and can be determined by the clinician.
  • the present disclosure relates to a method of sensitising cancer cells to an anti-cancer treatment comprising administering to a subject in need thereof an effective amount of a VRAC modulator.
  • the present disclosure relates to a method of potentiating the therapeutic effect of an anti-cancer treatment comprising administering to a subject in need thereof an effective amount of a VRAC modulator.
  • the present disclosure relates to a method for treatment of cancer comprising administering to a subject in need thereof an effective amount of a VRAC modulator and an effective amount of an anti-cancer treatment, such as a chemotherapeutic agent.
  • the present disclosure relates to a composition
  • a composition comprising an effective amount of a VRAC modulator and an effective amount of a chemotherapeutic agent for use as a medicament.
  • the present disclosure relates to a composition
  • a composition comprising an effective amount of a VRAC modulator and an effective amount of a chemotherapeutic agent for use in the treatment of cancer.
  • the present disclosure relates to a VRAC modulator for use in sensitising cancer cells to an anti-cancer treatment.
  • the present disclosure relates to a VRAC modulator for use in potentiating the therapeutic effect of an anti-cancer treatment.
  • the present disclosure relates to use of a VRAC modulator for the manufacture of a medicament for sensitising cancer cells to an anti-cancer treatment or for use in potentiating the therapeutic effect of an anti-cancer treatment.
  • the present disclosure relates to a kit of parts comprising a VRAC modulator and a chemotherapeutic agent, wherein the VRAC modulator and the chemotherapeutic agent are formulated for simultaneous, sequential or separate administration and optionally instructions for use.
  • the present disclosure relates to a VRAC modulator and an anti-cancer therapy, such as a chemotherapeutic agent, for use in the treatment of cancer in a subject, wherein said cancer has been determined to be resistant to treatment with said anti-cancer therapy.
  • Treatment with a VRAC modulator re-sensitises the resistant cancer cells to treatment with the anti-cancer therapy.
  • the resistance may be de novo resistance or acquired resistance.
  • Co-treatment with the VRAC modulator as described herein may be considered an adjuvant therapy to an anti-cancer treatment as the VRAC modulator maximises the effectiveness of the anti-cancer therapy.
  • treatment with a VRAC modulator as described herein may be considered a neoadjuvant therapy when administered before the anti-cancer treatment.
  • the tumour growth was retarded by inoculating only half the number of cells (2.5 million of C6 cells per animal) and making use of the subcutaneous air sac (SAS) technique.
  • SAS subcutaneous air sac
  • the rats were anaesthetized with CO 2 /O 2 and 10-15 ml of air was introduced dorsally by subcutaneous injections to produce an air sac located approximately 4-5 cm behind the head.
  • the wall of the air sac became progressively thicker with time and after 10-14 days a sufficient lining of cells with the appearance of a transparent membrane had been established.
  • the C6 glioma cells were inoculated in the rats directly on the membrane. The treatment was started at the day of inoculation and the study was terminated on day 10 of treatment.
  • the C6 cells exhibited less aggressive growth and oral administration of NS3728 (40 mg/kg/day) given either as monotherapy or in combination with temozolomide (5 mg/kg/day) produced a significant inhibition of tumour growth ( Fig. 2 ) while treatment with temozolomide alone did not result in a significant tumour growth inhibition as measured by tumour weight.
  • NS3728 The in vivo antitumor effect of NS3728 on the human HT29 colon cancer cell line were tested as monotherapy (80 mg/kg) respectively in combination with paclitaxel (5 mg/kg) or 5-flourouracil (30 mg/kg) in two independent experimental series.
  • NS3728 was given per oral (PO), whereas both paclitaxel and 5-flourouracil were dosed intraperitoneally (IP) by injection.
  • IP intraperitoneally
  • a human xenografted HT29 tumour exhibits increased sensitivity to the combination treatment of NS3728 and either 5-flourourecil or paclitaxel as compared to monotherapy with one of the chemotherapeutic drugs.
  • NS3728 is capable of potentiating the effect of 5-flourourecil and paclitaxel in vivo.
  • Example 3 Docetaxel and NS3728 in docetaxel resistant MCF-7 and MDA-MB231 human breast cancer cell lines.
  • breast cancer is a heterogenous disease and at least 6 subtypes of breast cancer have been described previously by Soerlie et al (PMID: 11553815). As a major difference, breast cancer can be divided into hormone (estrogen and progesterone) receptor positive and hormone receptor negative breast cancer. We have in our experiments included these two major subtypes.
  • DMSO did not affect cell viability of the docetaxel resistant MCF-7 breast cancer cells.
  • 65 nM of Docetaxel was chosen as this is the concentration to which the docetaxel resistant MCF-7 breast cancer cells were made resistant.
  • 65 nM Docetaxel and 40 ⁇ M NS3728 provided as monotherapy did not decrease cell viability.
  • the combination of 40 ⁇ M NS3728 and 65 nM Docetaxel resulted in a combinatory effect on cell viability for the docetaxel resistant MCF-7 breast cancer cells.
  • DMSO did not affect cell viability of Docetaxel resistant MDA-MB-231 breast cancer cells.
  • 150 nM of Docetaxel was chosen as this is the concentration to which the cells were made resistant.
  • 150 nM Docetaxel reduced the viability to about 50% of untreated controls.
  • 50 ⁇ M NS3728 did not decrease cell viability.
  • 50 ⁇ M NS3728 and 150 nM Docetaxel a combinatory effect on cell viability was observed for the Docetaxel resistant MDA-MB-231 breast cancer cells.
  • VRAC inhibitor NS3728 can enhance the effect of Docetaxel on Docetaxel resistant breast cancer cell lines.
  • NS3728 is capable of re-sensitising docetaxel-resistant cancer cells to treatment with Docetaxel.
  • Example 4 Oxaliplatin or SN38 and NS3728 in parental HCT116, HT29 and LoVo human colorectal cancer (CRC) cell lines.
  • CRC cells display genetic instability caused by chromosomal instability, microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), which result in activation of proto-oncogenes such as KRAS and inactivation of tumor suppressor genes such as TP53 (p53).
  • MSI microsatellite instability
  • CIMP CpG island methylator phenotype
  • KRAS proto-oncogenes
  • TP53 tumor suppressor genes
  • NS3728 as single drug or in combination with either OXP or SN-38 in the parental, i.e. drug-sensitive, cell lines.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • NS3728, OXP, SN-38 or combinations of NS3728 with one of the cytotoxic drugs were added for 48 hours before cell viability was determined. All values are expressed in percentage of untreated cells (named: "no treatment").
  • DMSO dimethyl sulfoxide
  • DMSO caused a minor reduction in cell viability of HCT116 parental cells.
  • NS3728 reduced cell viability to about 50% of untreated cells and OXP dose-dependently decreased cell viability of HCT116 parental cells.
  • Combinations of 40 or 50 ⁇ M NS3728 and 0.16/0.8/4/20 ⁇ m Oxaliplatin did not inhibit cell viability more than either monotherapy in HCT116 parental cells.
  • DMSO caused a minor reduction in cell viability.
  • NS3728 reduced cell viability to about 50% of untreated cells at two concentrations (40 and 50 ⁇ M).
  • SN-38 (0.16 ⁇ M) also decreased viability to about 50% of untreated cells.
  • the combinations of 40 or 50 ⁇ M NS3728 and 0.16 ⁇ M SN-38 had a combinatorial inhibitory effect on cell viability with the 40 ⁇ M NS3728 + SN-38 reducing cell viability to about 30% of untreated cells and the 50 ⁇ M NS3728 + SN-38 reducing cell viability to about 23% of untreated cells.
  • DMSO reduced cell viability in this cell line to about 78% of untreated cells.
  • NS3728 reduced cell viability to about 90% of untreated cells at 40 ⁇ M and to about
  • DMSO reduced cell viability in this cell line to about 75% of untreated cells.
  • NS3728 reduced cell viability to about 45% of untreated cells at 40 ⁇ M and to about 38% of untreated cells at 50 ⁇ M.
  • SN-38 (0.0064 ⁇ M) decreased viability to about 53% of untreated cells.
  • Combinations of 40 or 50 ⁇ M NS3728 and 0.0064 ⁇ M SN-38 caused a combinatorial inhibitory effect on cell viability with the 40 ⁇ M NS3728 + SN-38 reducing cell viability to about 35% of untreated cells and the 50 ⁇ M NS3728 + SN-38 reducing cell viability to about 22% of untreated cells.
  • VRAC inhibitor NS3728 can 1) inhibit CRC cell growth when administered as monotherapy and 2) enhance the effect of certain types of chemotherapy on human CRC cells. No combinatory effect of NS3728 and oxaliplatin was found. Thus, the results show that treatment with a VRAC inhibitor can potentiate the effect of certain types of chemotherapy.
  • Example 5 Oxaliplatin or SN-38 and NS3728 in oxaliplatin (OXP) or SN-38 resistant HCT116, HT29 and LoVo human colorectal cancer (CRC) cell lines.
  • OXP oxaliplatin
  • CRC LoVo human colorectal cancer
  • DMSO dimethyl sulfoxide
  • NS3728 does not seem to be capable of potentiating the therapeutic effect of oxaliplatin in oxaliplatin sensitive CRC cells which are resistant to SN-38.
  • DMSO had no effect on cell viability.
  • NS3728 (30 ⁇ M) reduced cell viability to about 85% of untreated cells and SN-38 (4 ⁇ M) had almost no effect on cell viability.
  • combinations of 4 ⁇ M SN-38 and 30 ⁇ M NS3728 caused a combined reduction in cell viability and thus significantly reduced cell viability to about 60%.
  • DMSO had no effect on cell viability.
  • NS3728 (30 ⁇ M) increased viability to about 120% of untreated cells.
  • NS3728 (40 ⁇ M) had no effect on cell viability and
  • NS3728 (50 ⁇ M) reduced viability to about 85% of untreated cells.
  • SN-38 (0.8 ⁇ M) reduced viability to about 78% of untreated cells.
  • Combinations of 0.8 ⁇ M SN-38 and 30/40/50 ⁇ M NS3728 caused a significant combined reduction in cell viability to less than 30% of untreated cells for all three NS3728 concentrations.
  • DMSO reduced cell viability in this cell line to about 80% of untreated cells.
  • NS3728 (30 ⁇ M) reduced viability to about 80% of untreated cells
  • NS3728 40 ⁇ M reduced viability to about 57%
  • NS3728 50 ⁇ M reduced viability to about 50% of untreated cells.
  • SN-38 (0.16 ⁇ M) reduced viability to about 78% of untreated cells. Combinations of 0.16 ⁇ M SN-38 and 30/40/50 ⁇ M NS3728 caused a significant combined reduction in cell viability to less than 20% of untreated cells for all three NS3728 concentrations.
  • DMSO caused essentially no change in cell viability.
  • NS3728 (20 ⁇ M) reduced viability to about 85% of untreated cells and SN-38 (0.1 ⁇ M) reduced viability to about 43% of untreated cells.
  • DMSO reduced viability to about 85% of untreated cells.
  • VRAC inhibitor NS3728 can enhance the effect of certain types of chemotherapy on resistant CRC cell lines.
  • NS3728 also enhanced the effect of SN-38 in cancer cells with acquired SN-38 resistance or with acquired oxaliplatin resistance.
  • the data suggests that NS3728 is capable of re-sensitising SN-38 drug-resistant cancer cells to treatment with SN-38.
  • Example 6 Tamoxifen or Fulvestrant in combination with NS3728 in tamoxifen resistant MCF-7/LCC2 or Fulvestrant MCF-7/LCC9 human breast cancer cell lines.
  • MCF-7 is an estrogen and progesterone receptor positive cell line.
  • 0.1 ⁇ M of Tamoxifen was chosen as this is the concentration which was shown in the original publication to cause only minor cell growth effects on MCF-7/LCC2 cells whereas growth of Tamoxifen sensitive cells were significantly more inhibited.
  • 40 ⁇ M NS3728 caused a minor reduction in cell viability to 70% of untreated control.
  • 0.1 ⁇ M Tamoxifen had no effect on the cell viability of the tamoxifen-resistant MCF-7/LCC2 cells.
  • the combination of 40 ⁇ M NS3728 and 0.1 ⁇ M Tamoxifen caused a strong and significant (P ⁇ 0.05) reduction of MCF-7/LCC2 cell viability to less than 40% of untreated cells ( Fig. 16 ).
  • 1 ⁇ M of Fulvestrant was chosen as this is the concentration that was applied in the original publication as the final concentration to establish the MCF-7/LCC9 cell line and this concentration is strongly inhibiting growth of Fulvestrant sensitive MCF-7 cells (Brünner et al, 1997, PMID 9270017).
  • 40 ⁇ M NS3728 caused a reduction in cell viability to 60% of untreated control.
  • 1 ⁇ M Fulvestrant had no effect on the cell viability of the fulvestrant-resistant MCF-7/LCC9 cells.
  • the combination of 40 ⁇ M NS3728 and 1 ⁇ M Fulvestrant caused a strong and significant (P ⁇ 0.05) reduction of MCF-7/LCC9 cell viability to 24% of untreated cells ( Fig. 17 ).
  • VRAC inhibitor NS3728 can enhance the effect of two types of anti-estrogens, namely Tamoxifen and Fulvestrant, on MCF-7 breast cancer cells that are made resistant to these types of anti-estrogens.
  • NS3728 is capable of re-sensitising anti-estrogen-resistant breast cancer cells to treatment with anti-estrogens, in particular to tamoxifen and fulvestrant.
  • mice used for the experiments are severely immunocompromised to prevent rejection of the human cancer cells.
  • the experimental set-up comprises three stages:
  • Stage 1 Growth of sensitive (parental) and docetaxel-resistant MDA-MB-231 cells
  • mice are inoculated with different numbers of the sensitive or the docetaxel-resistant MDA-MB-231 cells. This experiment determines the optimal number of cancer cells which is important for the subsequent dose-response experiments in Stages 2 and 3.
  • mice are treated with docetaxel when tumors have established.
  • Sensitive or docetaxel-resistant MDA-MB-231 cells are inoculated into mice, with cell numbers as determined from Stage 1. This experiment is important to demonstrate that cancer cells are also sensitive or resistant, respectively, in an in vivo setting.
  • parental and docetaxel-resistant MDA-MB-231 cells are inoculated into mice and treated with vehicle (control group), docetaxel alone, NS3728 alone or a combination of NS3728 and docetaxel.
  • tumor formation is monitored by palpation and measured by caliper.
  • Tumor volume is calculated and is plotted against time in a growth-curve. The mice are euthanized when the tumors are near maximal size (12 mm) or if the mice display any signs of discomfort or illness.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP19205104.3A 2016-05-17 2017-05-17 Combination treatment of cancer Active EP3622953B1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
RS20210510A RS61786B1 (sr) 2016-05-17 2017-05-17 Kombinovani tretman za kancer
EP21162597.5A EP3854393A1 (en) 2016-05-17 2017-05-17 Ns3728 for use in combination with temozolomide for the treatment of glioblastoma
PL19205104T PL3622953T3 (pl) 2016-05-17 2017-05-17 Leczenie skojarzone nowotworu
SI201730713T SI3622953T1 (sl) 2016-05-17 2017-05-17 Kombinirano zdravljenje raka
HRP20210572TT HRP20210572T1 (hr) 2016-05-17 2021-04-09 Kombinacijsko liječenje raka

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DKPA201670325 2016-05-17
PCT/EP2017/061823 WO2017198700A1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer
EP17726573.3A EP3458052B1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP17726573.3A Division EP3458052B1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP21162597.5A Division EP3854393A1 (en) 2016-05-17 2017-05-17 Ns3728 for use in combination with temozolomide for the treatment of glioblastoma

Publications (2)

Publication Number Publication Date
EP3622953A1 EP3622953A1 (en) 2020-03-18
EP3622953B1 true EP3622953B1 (en) 2021-03-17

Family

ID=58800797

Family Applications (3)

Application Number Title Priority Date Filing Date
EP21162597.5A Pending EP3854393A1 (en) 2016-05-17 2017-05-17 Ns3728 for use in combination with temozolomide for the treatment of glioblastoma
EP19205104.3A Active EP3622953B1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer
EP17726573.3A Active EP3458052B1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP21162597.5A Pending EP3854393A1 (en) 2016-05-17 2017-05-17 Ns3728 for use in combination with temozolomide for the treatment of glioblastoma

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP17726573.3A Active EP3458052B1 (en) 2016-05-17 2017-05-17 Combination treatment of cancer

Country Status (18)

Country Link
US (2) US11103481B2 (ja)
EP (3) EP3854393A1 (ja)
JP (1) JP7033554B2 (ja)
CN (1) CN109475535A (ja)
AU (1) AU2017266724B2 (ja)
BR (1) BR112018073518A2 (ja)
CA (1) CA3023202A1 (ja)
CY (2) CY1122541T1 (ja)
DK (2) DK3458052T3 (ja)
ES (2) ES2870805T3 (ja)
HR (2) HRP20200076T1 (ja)
HU (2) HUE047542T2 (ja)
LT (2) LT3458052T (ja)
PL (2) PL3622953T3 (ja)
PT (2) PT3622953T (ja)
RS (2) RS59844B1 (ja)
SI (2) SI3458052T1 (ja)
WO (1) WO2017198700A1 (ja)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3622953T (pt) * 2016-05-17 2021-04-21 Scandion Oncology As Tratamento combinado do cancro
WO2019165158A1 (en) * 2018-02-22 2019-08-29 University Of Florida Research Foundation, Incorporated Il-6 inhibitors and methods of treatment
EP3846802A1 (en) * 2018-09-06 2021-07-14 Scandion Oncology A/S Urea derivatives for use in the treatment of subjects with elevated expression and/or activity of srpk1
WO2020079051A1 (en) 2018-10-16 2020-04-23 Scandion Oncology A/S Compounds for treatment of microbial infection
AU2022292074A1 (en) 2021-06-14 2023-12-14 Scandion Oncology A/S Combination treatments for cancer patients and methods for identifying same
EP4104834A1 (en) 2021-06-14 2022-12-21 Scandion Oncology A/S Combination treatments for cancer patients and methods for identifying same
CA3221558A1 (en) 2021-06-14 2022-12-22 Peter Michael Vestlev Methods of increasing the plasma drug exposure of anticancer agents
TW202321205A (zh) 2021-07-16 2023-06-01 丹麥商斯坎丁腫瘤公司 Sco-101的熱力穩定形式
EP4197525A1 (en) 2021-12-20 2023-06-21 Scandion Oncology A/S Combination of drugs for the treatment of cancer
CN117229258B (zh) * 2022-06-07 2024-07-19 杭州壹瑞医药科技有限公司 N-四唑基芳基脲类衍生物及其制备方法和应用
WO2023242235A1 (en) 2022-06-14 2023-12-21 Scandion Oncology A/S Abcg2 inhibitor and nae inhibitor for the treatment of cancer
WO2024013058A1 (en) 2022-07-11 2024-01-18 Scandion Oncology A/S Salts of sco-101 and methods involving salts

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5004758A (en) * 1987-12-01 1991-04-02 Smithkline Beecham Corporation Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells
DK0977741T3 (da) 1997-04-22 2003-12-01 Neurosearch As Substituerede phenylderivater, deres fremstilling og anvendelse
EP1514867A3 (en) 1998-10-22 2005-03-23 NeuroSearch A/S Substituted phenyl derivatives, their preparation and use
IL166040A0 (en) 2002-08-01 2006-01-15 Neurosearch As Compounds useful for the treatment of diseases responsive to antiangiogenetic therapy
WO2004111017A1 (en) 2003-06-17 2004-12-23 Neurosearch A/S Diphenylurea derivatives and their use as chloride channel blockers
JP2007520525A (ja) 2004-02-04 2007-07-26 ノイロサーチ アクティーゼルスカブ 二量体のアザ環式化合物及びその使用
JP2008524158A (ja) 2004-12-17 2008-07-10 ノイロサーチ アクティーゼルスカブ カリウムチャネル活性化剤として有用なジフェニル尿素誘導体
JP2009530238A (ja) * 2006-03-14 2009-08-27 ノイロサーチ アクティーゼルスカブ ジフェニル尿素誘導体及び塩化物チャネル遮断薬又はＢＫＣａチャネル調節薬としてのその使用
JO2885B1 (en) * 2008-12-22 2015-03-15 ايلي ليلي اند كومباني Protein kinase inhibitors
TWI508954B (zh) * 2012-04-27 2015-11-21 Nat Defense Medical Ct 雜環融合蒽醌衍生物、其製備方法與醫藥組合物
EP2919009B1 (en) 2014-03-10 2018-09-19 Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft LRRC8 proteins and protein complexes and methods for identification of channel modulators
ES2662822T3 (es) 2015-03-04 2018-04-09 Scandion Oncology A/S Derivados de 4-amino-3-fenilamino-6-fenilpirazol[3,4-d]pirimidina para uso como inhibidores de la BCRP en tratamientos terapéuticos
PT3622953T (pt) * 2016-05-17 2021-04-21 Scandion Oncology As Tratamento combinado do cancro

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
HRP20200076T1 (hr) 2020-04-03
US11903927B2 (en) 2024-02-20
ES2770374T3 (es) 2020-07-01
DK3458052T3 (da) 2020-02-03
BR112018073518A2 (pt) 2019-03-19
EP3458052A1 (en) 2019-03-27
WO2017198700A1 (en) 2017-11-23
SI3622953T1 (sl) 2021-05-31
HUE047542T2 (hu) 2020-04-28
SI3458052T1 (sl) 2020-04-30
CY1122541T1 (el) 2021-01-27
HUE053744T2 (hu) 2021-07-28
RS59844B1 (sr) 2020-02-28
DK3622953T3 (da) 2021-04-26
JP7033554B2 (ja) 2022-03-10
CN109475535A (zh) 2019-03-15
PL3622953T3 (pl) 2021-08-16
US11103481B2 (en) 2021-08-31
AU2017266724B2 (en) 2022-04-14
CY1124242T1 (el) 2022-07-22
JP2019519506A (ja) 2019-07-11
RS61786B1 (sr) 2021-06-30
EP3854393A1 (en) 2021-07-28
US20210353596A1 (en) 2021-11-18
EP3622953A1 (en) 2020-03-18
LT3458052T (lt) 2020-02-10
PT3458052T (pt) 2020-02-03
HRP20210572T1 (hr) 2021-05-14
PT3622953T (pt) 2021-04-21
ES2870805T3 (es) 2021-10-27
PL3458052T3 (pl) 2020-06-29
AU2017266724A1 (en) 2018-12-20
LT3622953T (lt) 2021-04-26
EP3458052B1 (en) 2019-11-06
US20190269654A1 (en) 2019-09-05
CA3023202A1 (en) 2017-11-23

Similar Documents

Publication Publication Date Title
US11903927B2 (en) Combination treatment of cancer
JP6621501B2 (ja) 新規癌治療法としてのアリール炭化水素受容体（ＡｈＲ）改変物質
JP6678585B2 (ja) Ｅｒｋ阻害剤およびｒａｆ阻害剤の組み合わせを使用するがん処置
EP2694071B1 (en) Combinations of akt inhibitor compounds and chemotherapeutic agents, and methods of use
KR102473113B1 (ko) 암 치료를 위한 병용 요법
US20180085348A1 (en) Methods for treating cancer with rorgamma inhibitors
JP6570512B2 (ja) 新規なＳｔａｔ３阻害剤
EP2694073B1 (en) Combinations of akt and mek inhibitors for treating cancer
KR20190025733A (ko) 원발성 호르몬 저항성 자궁내막암 및 유방암 치료 방법 및 약학적 조성물
EP3846802A1 (en) Urea derivatives for use in the treatment of subjects with elevated expression and/or activity of srpk1
EP4197525A1 (en) Combination of drugs for the treatment of cancer
RU2801665C2 (ru) Фармацевтическая комбинация для лечения рака
BR112021016747A2 (pt) Método para tratamento de um meloma múltiplo

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED

AC Divisional application: reference to earlier application

Ref document number: 3458052

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200917

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602017035042

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0031424500

Ipc: A61K0031474500

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 271/07 20060101ALI20201124BHEP

Ipc: A61K 31/4745 20060101AFI20201124BHEP

Ipc: A61K 31/4245 20060101ALI20201124BHEP

Ipc: C07D 257/04 20060101ALI20201124BHEP

Ipc: A61P 35/02 20060101ALI20201124BHEP

Ipc: A61K 31/41 20060101ALI20201124BHEP

Ipc: A61P 35/04 20060101ALI20201124BHEP

Ipc: A61P 35/00 20060101ALI20201124BHEP

INTG Intention to grant announced

Effective date: 20201208

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40026430

Country of ref document: HK

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AC Divisional application: reference to earlier application

Ref document number: 3458052

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602017035042

Country of ref document: DE

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20210572T

Country of ref document: HR

REG Reference to a national code

Ref country code: FI

Ref legal event code: FGE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1371595

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210415

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 3622953

Country of ref document: PT

Date of ref document: 20210421

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20210414

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20210421

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: STOLMAR AND PARTNER INTELLECTUAL PROPERTY S.A., CH

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20210572

Country of ref document: HR

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20210572

Country of ref document: HR

Payment date: 20210427

Year of fee payment: 5

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 37046

Country of ref document: SK

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E020668

Country of ref document: EE

Effective date: 20210416

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20210317

Ref country code: GR

Ref legal event code: EP

Ref document number: 20210401020

Country of ref document: GR

Effective date: 20210614

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E053744

Country of ref document: HU

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2870805

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20211027

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602017035042

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20211220

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 1371595

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210317

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20210572

Country of ref document: HR

Payment date: 20220426

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SM

Payment date: 20220504

Year of fee payment: 6

Ref country code: RS

Payment date: 20220427

Year of fee payment: 6

Ref country code: MC

Payment date: 20220429

Year of fee payment: 6

Ref country code: LU

Payment date: 20220513

Year of fee payment: 6

Ref country code: LT

Payment date: 20220502

Year of fee payment: 6

Ref country code: HR

Payment date: 20220426

Year of fee payment: 6

Ref country code: EE

Payment date: 20220516

Year of fee payment: 6

Ref country code: BG

Payment date: 20220511

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20220426

Year of fee payment: 6

Ref country code: LV

Payment date: 20220523

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MT

Payment date: 20220504

Year of fee payment: 6

Ref country code: IS

Payment date: 20220429

Year of fee payment: 6

REG Reference to a national code

Ref country code: HU

Ref legal event code: HC9C

Owner name: SCANDION ONCOLOGY A/S, DK

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20220428

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AL

Payment date: 20220509

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MK

Payment date: 20220427

Year of fee payment: 6

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230525

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20210572

Country of ref document: HR

Effective date: 20230517

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20230517

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E020668

Country of ref document: EE

Effective date: 20230531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20231212

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230518

Ref country code: RS

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230531

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

Ref country code: HR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230531

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230517

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20240228

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20240526

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20240527

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20240527

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240530

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20240527

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20240530

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20240602

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240603

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20240503

Year of fee payment: 8

Ref country code: CZ

Payment date: 20240507

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20240502

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: RO

Payment date: 20240507

Year of fee payment: 8

Ref country code: NO

Payment date: 20240530

Year of fee payment: 8

Ref country code: FR

Payment date: 20240527

Year of fee payment: 8

Ref country code: FI

Payment date: 20240527

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20240506

Year of fee payment: 8

Ref country code: PT

Payment date: 20240502

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20240503

Year of fee payment: 8

Ref country code: SE

Payment date: 20240527

Year of fee payment: 8

Ref country code: HU

Payment date: 20240509

Year of fee payment: 8

Ref country code: BE

Payment date: 20240527

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20240521

Year of fee payment: 8